Bristol-Myers Squibb saw nearly a quarter of the value wiped off its shares late last week after it revealed a major setback for fast-growing PD-1 inhibitor Opdivo.
A phase III trial of the immuno-oncology drug revealed it was unable to improve progression-free survival (PFS) when used as a first-line treatment for patients with advanced non-small cell lung cancer.
The disappointing result is a blow to patients and their doctors as it reveals cracks in the armour of the new generation of cancer immunotherapies, which have achieved a string of successes in trials to date.
It also hands an opportunity to arch-rival Merck & Co, whose PD-1 inhibitor Keytruda (pembrolizumab) reportedly improved both PFS and overall survival in this setting in a phase III trial reported in June.
Keytruda was first to be approved in the US but has lagged behind Opdivo in sales terms, thanks largely to a faster roll-out in new indications. Opdivo is approved for melanoma, second-line NSCLC treatment, renal cell carcinoma and relapsed classical Hodgkin lymphoma, while Keytruda is currently registered only for melanoma and second-line NSCLC.
Merck’s decision to carefully select patients in its studies whose tumours express PD-L1, a ligand that binds to PD-1 on cancer cells, has also not been in its favour to date. BMS has benefited from using a broader recruitment strategy in pivotal trials as NSCLC patients can be treated with the drug regardless of PD-L1 status.
That strategy may now have backfired, however. BMS’ CheckMate-026 study had a similar design to the Merck trial, comparing the PD-1 inhibitor with first-line chemotherapy. On this occasion BMS also selected patients with PD-L1-positive tumours, but the threshold used in the two studies was markedly different, which might explain the divergence in results.
In Merck’s case patients were recruited if 50% or more of the tumour cells expressed PD-L1, while in BMS’ trial the threshold for inclusion was just 5%. It is not unreasonable to suggest that in the first-line NSCLC setting, PD-L1 status assumes greater clinical importance.
The reason for the diverging performance of the two drugs will take some time to tease out from the data sets, but in the meantime analysts have said it will lend momentum to Keytruda, potentially adding $1bn-plus to peak sales forecasts of $5bn.
BMS is reporting $1.54bn in sales for Opdivo in the first half of 2016, some way ahead of the $563m achieved by Keytruda in the same period.
“We designed our development programme in lung cancer to address the unmet need of every lung cancer patient and our scientific approach is a bold one,” said BMS in a statement.
The company also has a trial studying the combination of Opdivo and Yervoy (ipilimumab) in first-line NSCLC that it hopes will support its use as an all-comer therapy, regardless of PD-L1 status.